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Histone deacetylase inhibition accelerates the early events of stem cell differentiation: transcriptomic and epigenetic analysis

Efthimia Karantzali12, Herbert Schulz3, Oliver Hummel3, Norbert Hubner3, AK Hatzopoulos45 and Androniki Kretsovali1*

Author Affiliations

1 Institute of Molecular Biology and Biotehnology, FORTH, Heraklion 71110 Greece

2 Department of Biology, University of Crete, Heraklion 71409 Greece

3 Max-Delbruck-Center for Molecular Medicine-MDC, Berlin 13092, Germany

4 GSF, Institute of Clinical Molecular Biology and Tumor Genetics, 81377 Munich, Germany

5 Vanderbilt University, Department of Medicine - Division of Cardiovascular Medicine and Department of Cell and Developmental Biology, Nashville Nashville, TN 37232-2358, USA

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Genome Biology 2008, 9:R65  doi:10.1186/gb-2008-9-4-r65

Published: 4 April 2008

Abstract

Background

Epigenetic mechanisms regulate gene expression patterns affecting cell function and differentiation. In this report, we examine the role of histone acetylation in gene expression regulation in mouse embryonic stem cells employing transcriptomic and epigenetic analysis.

Results

Embryonic stem cells treated with the histone deacetylase inhibitor Trichostatin A (TSA), undergo morphological and gene expression changes indicative of differentiation. Gene profiling utilizing Affymetrix microarrays revealed the suppression of important pluripotency factors, including Nanog, a master regulator of stem cell identity, and the activation of differentiation-related genes. Transcriptional and epigenetic changes induced after 6-12 hours of TSA treatment mimic those that appear during embryoid body differentiation. We show here that the early steps of stem cell differentiation are marked by the enhancement of bulk activatory histone modifications. At the individual gene level, we found that transcriptional reprogramming triggered by histone deacetylase inhibition correlates with rapid changes in activating K4 trimethylation and repressive K27 trimethylation of histone H3. The establishment of H3K27 trimethylation is required for stable gene suppression whereas in its absence, genes can be reactivated upon TSA removal.

Conclusion

Our data suggest that inhibition of histone deacetylases accelerates the early events of differentiation by regulating the expression of pluripotency- and differentiation-associated genes in an opposite manner. This analysis provides information about genes that are important for embryonic stem cell function and the epigenetic mechanisms that regulate their expression.